Using limiting dilution culture, EBV transformation and somatic hybridization techniques, cell lines capable of making human monoclonol antibodies to a number of self-antigens, e.g., ssDNA, thyroglobulin, insulin, Fc fragment of IgG, and exogenous antigens, e.g., tetanus toxoid, HIV, have been established. These technologies have been applied to the study of the human B cell repertoire in patients with systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's disease. B lymphocytes producing two groups of autoantibodies were detected in these patients. The first one includes autoantibodies binding to multiple self and exogenous antigens, in general, with low affinity - polyreactive antibodies which can be detected also in healthy subjects. The second one includes high affinity monoreactive autoantibodies and is exclusive of autoimmune patients. Using fluorescence-activated cell sorter, the B lymphocytes devoted to production of polyreactive "autoantibodies" were identified as a discrete (CD5+) B cell subset. The role of CD5+ B lymphocytes and that of other B cells in the human immune response to rabies virus have been investigated. lt was found that the B cells recruited during a primary antibody response are committed to the production of polyreactive antibodies, mainly of the IgM class, and are indeed CD5+. In sharp contrast, the B cells recruited in a secondary or tertiary immunization belong to the CD5- compartment and produce antibodies, mainly IgG, which are monoreactive and specific for the inducing antigen. The difference in affinity between the "primary" antibodies and "secondary" antibodies can be as much as 1,000 times. Current experiments will possibly clarify whether this tremendous enhancement in affinity is achieved through accumulation of somatic point mutations and/or rearrangement of different gene segments coding for the regions of the antibodies.